The natural hormone, 1α,25-dihydroxyvitamin D3 and its analog in ergosterol series (i.e., 1α,25-dihydroxyvitamin D2) are known to be highly potent regulators of calcium homeostasis in animals and humans. More recently, it has been reported that their activity in cellular differentiation has been established. (Ostrem et al., 1987, Proc. Natl. Acad. Sci. USA, 84, 2610). Many structural analogs of these metabolites have been prepared and tested, including 1α-hydroxyvitamin D3, 1α-hydroxyvitamin D2, various side chain homologated vitamins and fluorinated analogs. Some of these compounds exhibit an interesting separation of activities in cell differentiation and calcium regulation. Such differences in activity may be useful in the treatment of a variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and certain malignancies.
In 1990, a new class of vitamin D analogs was discovered. The so-called 19-nor-vitamin D compounds were reported, which have been characterized by the replacement of the ring A exocyclic methylene group (carbon 19) (typical of the vitamin D system) by two hydrogen atoms. Biological testing of such 19-nor analogs (e.g., 1α,25-dihydroxy-19-nor-vitamin D3) have revealed a selective activity profile having high potency to induce cellular differentiation with very low calcium mobilizing activity.
Thus, these 19-nor analog compounds have been potentially useful as therapeutic agents for the treatment of malignancies and/or various skin disorders. Two different methods of synthesis of such 19-nor-vitamin D analogs have been reported. (Perlman et al., 1990, Tetrahedron Letters 31, 1823); Perlman et al., 1991, Tetrahedron Letters 32, 7663); and, U.S. Pat. No. 5,086,191 to DeLuca et al.). A few years later, synthesis of analogs of 1α,25-dihydroxy-19-norvitamin D3 substituted at 2-position with hydroxy or alkoxy groups were reported. (U.S. Pat. No. 5,536,713 to DeLuca et al.) These 19-nor-vitamin D compounds also exhibit interesting and selective activity profiles. Binding sites in vitamin D receptors can accommodate different substituents at C-2 in the synthesized vitamin D analogs.
Recent synthesis and testing of the 19-nor class of pharmacologically important vitamin D compounds has been reported, whereby the analogs are characterized by the transposition of the ring A exocyclic methylene group from carbon 10 (C-10) to carbon 2 (C-2) (i.e., 2-methylene-19-nor-vitamin D compounds have been recently synthesized and tested). (Sicinski et al., 1998, J. Med. Chem., 41, 4662; Sicinski et al., 2002, Steroids 67, 247; and, U.S. Pat. Nos. 5,843,928, 5,936,133 and 6,392,071, each to DeLuca et al.).
Molecular mechanics studies, performed on these analogs, showed that a change of A-ring conformation can be expected resulting in the “flattening” of the cyclohexanediol ring. From molecular mechanics calculations and NMR studies their A-ring conformational equilibrium was established to be ca. 6:4 in favor of the conformer that has an equatorial 1α-OH. Introduction of the 2-methylene group into 19-nor-vitamin D carbon skeleton changes the character of its (1α- and 3β-) A-ring hydroxyls. They are both now in the allylic positions, similar to the 1α-hydroxyl group (crucial for biological activity) in the molecule of the natural hormone, 1α,25-(OH)2D3. It was found that 1α,25-dihydroxy-2-methylene-19-norvitamin D analogs are characterized by significant biological potency, enhanced dramatically in compounds with “unnatural” (20S)-configuration.
An interesting modification of the vitamin D skeleton is removal of its C and D rings. The first compound (retiferol) lacking the C,D-substructure, was obtained thirteen years ago (Kutner et al., 1995, Bioorg. Chem. 23, 22). Later, several des-C,D vitamin D3 derivatives, including 19-nor analogs, were synthesized. (Bauer et al., U.S. Pat. No. 5,969,190; and, Barbier et al., U.S. Pat. No. 6,184,422) and some compounds (Ro 65-2299) showed improved biological activities. (Hilpert et al., 2001, Tetrahedron 57, 681).
Recently, biological testing and synthesis of des-C,D analog of 2-methylene-1α,25-dihydroxy-19-norvitamin D3 have been reported. (DeLuca et al., U.S. Pat. Appl. Publ. No. US 2007/0112077). The analog retained some VDR binding ability and transcriptional activity albeit significantly decreased in comparison to the analogous vitamins possessing intact C,D rings.